Novel carbonates

ABSTRACT

MIXED CARBONATES OF 9A-FLUORO-16A-METHYL-17A-R-$1,4PREGNADIENE-11B-21-DIOL-3,20-DIONE OF THE FORMULA   9-F,11-HO,16-CH3,17-R,22(CH3-CH2-O-(CH2-CH2-O)N-CH2-CH2-   OOC-O-)-1,4-PREGNADIENE-3,20-DIONE   WHEREIN N IS AN INTEGER FROM 0 TO 10 AND R IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND HYDROXYL HAVING ANTI-INFLAMMATORY ACTIVITY AND THEIR PREPARATION.

United States Patent M Int. (:1. (36% 169/32 US. Cl. 260-39145 ClaimsABSTRACT OF THE DISCLOSURE 0:0 0 emotion-o on orn 110? a I i-on a (I)wherein n is an integer from 0 to and R is selected from the groupconsisting of hydrogen and hydroxyl having anti-inflammatory activityand their preparation.

OBJECTS OF THE INVENTION The novel products of the invention are mixedcarbonates of poly B-ethoxyethyl and 9a-fluoro-l6a-methyll7a- .R-A-pregnadiene-I1,8,21-diol-3,20-dione of the formula Particularlyinteresting are the mixed carbonates of (a) ,lY-ethoxy-fl-ethoxyethyland dexamethasone, (b) ,8"- ethoxy-,B'-ethoxy-,B-ethoxyethyl anddexamethasone, (0)

3,591,612 Patented July 6, 1971 ,B-ethoxyethyl and dexamethasone and (d)B-ethoxyethyl and 9m fluoro-16a-methyl-A -pregnadiene-l15,21-diol-3,20-dione.

The novel process of the invention for the preparation of the novelmixed carbonates of Formula I comprises condensing a chloroformate ofthe formula.

wherein n has the above definition with a steroid of the formula CHzOH(III) wherein R has the above definition in an organic solvent such asdioxane in the presence of a tertiary base such as pyridine.

The novel anti-inflammatory compositions are comprised of an effectiveamount of at least one mixed carbonate of Formula I and a major amountof a pharmaceutical carrier. The compositions may be in the form ofinjectable solutions or suspensions in the form of ampules or multipledose fiacons, sterile powders for extemporaneous use, suppositories,ointments, creams, collyrium, nose and ear drops, topical pulverizedpowders solid or liquid aerosol sprays in pressurized containers' ovulesand vaginal creams.

The compositions have an important anti-inflammatory activity and areparticularly useful for the treatment of local inflammatory orpruriginous manifestations. They are useful for the treatment ofradicular algias, acute or chronic polyarthritis, acute of chronicrheumatic complaints and lumbar sciaticas. Due to their ether/waterdistribution coefficient and their ether/water solubility ratio, theyare particularly suitable for topical application.

The novel method of treating inflammation in warmblooded animalscomprises administering to warmblooded animals an elfective amount of atleast one carbonate of Formula I. The said carbonates may beadministered transcutaneously, rectally or topically to local skin areasor mucous membranes. The preferred concentration of the active compoundis 0.01% to 1%.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE I Mixed carbonate of /i-ethoxy-[3-ethoxyethyl and dexamethasone5 gm. of dexamethasone were added to a mixture of 10 cc. of pyridine and25 cc. of dioxane and after cooling to 0 C., a solution of 2.9 gm. ofB-ethoxy-p-ethoxyethyl chloroformate in 15 cc. of dioxane was addedthereto. The mixture was stirred at 0 C. for 30* minutes and overnightat room temperature. Excess ,8'-ethoxy-,6-ethoxyethyl chloroformate wasdestroyed by the addition of a few drops of water and then the reactionmixture was poured into a mixture of ice-water and hydrochloric acid.The mixture was extracted with methylene chloride and the organic phasewas washed with water until the wash waters were neutral, dried oversodium sulfate and evaporated to dryness in vacuo. The 6.7 gm. of cruderesidue was recrystallized from hot and cold methanol to obtain 5.4 gm.(76.5% yield) of the mixed carbonate of 13- ethoxy-fi-ethoxyethyl anddexamethasone having a melting point of 123-125 C. and specific rotation[a] +79i2 (c.:0.5% in dioxane). The product was soluble in acetone,benzene and chloroform, slightl soluble in alcohol and ether andinsoluble in water.

A,nalysis.Calculated for C H FO (molecular weight=552.62), (percent): C,63.02; H, 7.48; F, 3.44. Found (percent): C, 63.1; H, 7.8; F, 3.6.

As far as is known, this compound is not described in the literature.

/3-Ethoxy-fi-ethoxyethyl chloroformate was prepared by the process ofMacko, Chem. Zvest, vol. 13 (1959), p. 436.

EXAMPLE II Mixed carbonate of B-ethoxyethyl and dexamethasone Using theprocess of Example I, 5 gm. of dexamethasone and 2.92 gm. ofB-ethoxyethyl chloroformate were reacted to obtain 6.22 gm. of the mixedcarbonate of ethoxyethyl and dexamethasone having a melting point of 218C. and a specific rotation [a] :+82i2.5 (c.= 0.5% in dioxane).

The product was soluble in chloroform, slightly soluble in alcohol,benzene and ether, fairly soluble in acetone and insoluble in water.

Analysis-Calculated for C H FO (molecular weight=508.57), (percent): C,63.76; H, 7.33; F, 3.74. Found (percent): C, 64.1; H, 7.5; F, 3.7.

As far as is known, this compound is not described in the literature.

fl-Ethoxyethyl chloroformate was prepared by the process of Ashburn, J.Am. Soc., vol. 60 (1938), p. 2933.

EXAMPLE III Mixed carbonate of fi-ethoxyethyl and 9a-fluoro-16amethyl-A-pregnadiene-11 8,21-diol-3,20-dione Using the process of Example I, 2gm. of 9a-fiuoro- 16a-methyl-A -pregnadiene-l1B,21-diol-3,20 dione and1.21 gm. of fi-ethoxyethyl chloroformate were reacted to obtain 2.6 gm.of the mixed carbonate of ,B-ethoxyethyl and 9a-fluoro-16a-methyl Apregnadiene-11B,21-diol- 3,20-dione having a melting point of 130 C. anda specific rotation [a] =+113.5i2 (c.==l.05% in chloroform) The productwas soluble in alcohol, acetone and chloroform, fairly soluble in ether,slightly soluble in benzene and insoluble in water.

Analysis.Calculated for C27H37FO7 (molecular Weight=492.56) (percent):C, 65.83; H, 7.57; F, 3.86. Found (percent): C, 65.8; H, 7.7; F, 4.0.

As far as is known, this compound is not described in the literature.

EXAMPLE IV Mixed carbonate of [3"-ethoxy-fl'-ethoxy-fl-ethoxyethyl anddexamethasone Step A: 8"-ethoxy-B'-ethoxy-[B-ethoxyethylchloroformate.30 cc. of toluene were added to 72.5 cc. of a 31% solutionof phosgene in toluene with stirring under nitrogen and at roomtemperature and after the addition of 17.8 gm. of triethylene glycolmonoethylether in 60 cc. of benzene, the reaction mixture was stirred atroom temperature for 18 hours. Excess phosgene and the hydrochloric acidformed were removed by a current of nitrogen and the benzene and toluenewere evaporated off. The residue was distilled to obtain 16 gm. of[3-ethoxy-fi'- 4 ethoxy-fl-ethoxyethyl chloroformate as a colorlessliquid boiling at 106-109 C. at 0.9-1.1 mm. Hg.

Step B: Mixed carbonate.2 gm. of dexamethasone were suspended in 4 cc.of pyridine and 10 cc. of dioxane at an internal temperature of 0 to 2C. under a nitrogen atmosphere and after the addition of a solution of1.85 gm. of B"-ethoxy-;8'-ethoxy-[i-ethoxyethyl chloroformate in 6 cc.of dioxane, the reaction temperature was raised to 20 C. and the mixturewas stirred for 18 hours still under a nitrogen atmosphere. Excesschloroformate was destroyed by the addition of a few drops of water andthe reaction mixture was poured into a solution of 4.8 cc. ofhydrochloric acid in cc. of water. After decanting off the liquid, theprecipitate was dissolved in ether and the ether phase was washed withwater and distilled to dryness. The residue was dissolved in 1 cc. ofhot ethanol to which isopropyl ether was added at C. to beginprecipitation. After ice cooling, the mixture was vacuum filtered. Theprecipitate was washed with an iced mixture of ethanol/isopropyl etherand dried to obtain 2.345 gm. of mixed carbonate of,8"-ethoxy-fi-ethoxy-fl-ethoxyethyl and dexamethasone melting at 89 C.Letting the decanted mother liquid stand gave an additional 0.405 gm. ofproduct melting at 90 C. for a total yield of 89%. Recrystallization ofthe product from ethanol-isopropyl ether gave a product melting at 89.5C. and a specific rotation [a] =|-83 (c.=0.5% in ethanol). The productwas soluble in alcohol, ether and chlorinated solvents and insoluble inwater.

Analysis.Calculated for C H O F (molecular weight=596.69) (percent): C,62.39; H, 7.60; F, 3.18. Found (percent): C, 62.3; H, 7.9; F, 3.4.

UV. spectrum (ethanol):

A max at 239-240 m e=16,000 IR. spectrum (chloroform):

Presence of -OH Presence of A -3-one Presence of carbonyl at 1,751 and1,732

As far as is known, this product is not described in the literature.

EXAMPLE V 0.25 g. of the active product was added to 10 gm. of propyleneglycol, 37 gm. of polyoxyethylene glycol 3000, 11 gm. of polyoxyethyleneglycol 4000 and sufficient polyoxyethylene 1,540 to make a total of gm.

The dosage of active ingredient is expressed in molecular equivalent ofthe corresponding free alcohol.

PHARMACOLOGICAL DATA (A) Anti-inflammatory activity The subcutaneousanti-inflammatory activity of the carbonates of Formula I was determinedwith the granuloma test with cotton using the technique of Singer,Proceed. Soc. Exp. Biol. Med., vol. 92 (1956), p. 23 as modified byArth, J.A.C.S., vol. 80 (1958), p. 3161. Female rats weighing 100 to gm.received a ventral bilateral subcutaneous implantation of a coton pelletweighing about 10 mg. The test products were then administeredsubcutaneously morning and evening for 2 consecutive days with the firstimmediately following the implantation. On the 3rd day, 17 hours afterthe last administration, the rats were sacrificed and the pellets withthe granuloma tissue which encircled them were cut out and weighed. Thedry granuloma weight was determined by subtracting the weight of thecotton and the weights of the granuloma of the pellet impregnated withthe product under study were expressed as a percentage of the weight ofthe granuloma of the control pellets. The thymus gland was also removedand weighed to determine the thymolytic activity. The products wereadministered in aqueous suspension and were compared to dexamethasone ordexamethasone acetate. The controls received only the aqueoussuspension. The results are reported in Table I.

TABLE I Dried granuloma Thymus Doses in Weight; Percent Weight PercentProduct 'y/kg. in mg. protection in mg. involution Controls 48. 9 272Mlxed carbonate oi ;8-ethoxy-B-ethor ethyl and dcxamethasone 70. 5 26. 146 147 16 Dexamethasone 50 9. 9 39 117 57 hoxyethyl and dexamethaso 14117.5 64 86 69 100 17.9 63 97 64 Controls 67. 5 299 Mixed carbonate ofB"-eth0Xy-B-cthoxy-B-ethoxyethyl and dexamethasone 76 46. 1 32 141 52Dexamethasone acetate 55 7- 2 30 136 55 The results of Table I show thatthe thymolytic and TABLE II the anti-inflammatory activity of the mixedcarbonate of fi"-ethoXy-fl-ethoxy-fl-ethoxyethyl and dexamethasone is liy R equal to dexamethasone acetate and that the thymolytic 'i 322, andthe anti-inflammatory activity of the mixed carbonate Products EtherWater water of ,8'-ethoxy ,B-ethoxyethyl and dexamethasone is equal toMixectlhearbonate of fi-ethoxyethyl and dexame 2150119 dexamethasoneMgred cargjouateoffi -ethoxyethyl and 604 5 116 exame ascne 2 2 2 a- (B)Transcutaneous action on rats determmed by theMhgdfarbgrateofBEethoxy-Bcthoxy-fl-ethoxy- 80 10 W e y an exarnct asone6,40 thymolytlc effect Miied cargonateoffl-ethoxyethyl and QQbI'lUOKO 026 246 The thymolytic effect in the rat was determined after gmwkggo' 4455 28 159 cutaneous applications of 3'-ethoXy-fl-ethoXyethyl andDexamethasone acetate" '47s 17 27 dexamethasone miXed carbonate incomparison with dexamethasone acetate, both products being administeredin the form of a 0.25% ointment (concentration expressed indexamethasone) Various modifications of the compositions and methodoffhe lnventlon may be made without departing from the spirit or scopethereof.

Male rats weighing 160-170 gm. each were depilated 30 We Claim: in thecervical region under anesthesia with ether on the A ITllXed Carbonate0f the formula day prior to the experiment. They received two applica- 0tions per day of the ointment containing the said com- 7 H pound for 2days, the ointment being applied by massag- (;3H2 O CAO OH2 CH2 ing thedepilated area with the ointment for about 30 sec- 2 2)I1O CHZOHS onds.The rats were sacrificed on the third day and the HO thymus glands wereremoved and weighed.

This treatment corresponded with the administration A g of 45 .tg. ofactive compound per kg. of body weight per i application (dose expressedin dexamethasone). A de- O F crease in weight of the thymus glands ofabout 50% was ascertained by comparison with the weight of the thymusglands as determined in the control rats. The results showedsatisfactory cutaneous penetration of the said product.

(C) Solubility of the products of the invention in ether and water Thedeterminant importance of solubility ratios for transcutaneouspenetration has frequently been emphasized. Recently, the solubilityproperties of several cortisone compounds were studied by Katz et al.,J. Pharm. Sci., 1965, 54, 581 and a probant correlation was made evidentas to the percutaneous activity in human and the product between theether/water partition coeflicient and the aqueous solubility.

The separated solubility of the products under investigation in etherthen in water was determined. The quantities of dissolved product weredosed by spectrophotometry upon saturation under standard conditions.The results are given in Table II.

(I) wherein n is an integer from 0 to 10 and R is selected from thegroup conslsting of hydrogen and hydroxyl.

2. it compound of claim 1 wherein R is hydroxyl and n is 5i. (1?compound of claim 1 wherein R is hydroxyl and n is 4. x compound ofclaim 1 wherein R is hydroxyl and 11. 1s

5. 6K compound of claim 1 wherein R is hydrogen and n 1s ELBERT L.ROBERTS, Primary Examiner US. Cl. X.R. 424-243 Patent No. 3,591 612Dated July 6, 1971 Inventor: Andre Allais It is certified that errorappears in the above identified patent and that said Letters Patent arehereby corrected as shown below:

Column 2, formula III should read as follows:

fH OH O -R Column 3, line 30 After "82" insert degree sign Column 4 line59 Correct spelling of "cotton" Column 6, claim 1, Formula should read:

H -O-C-O-CH -CH -(OCH2CH n-0CH CH Signed and sealed this 15th day ofFebruary 1972.

(SEAL) Attest:

EDWARD M.-FLETCHER,JR. I ROBERT GOTTSCHALK Attesting OfficerCommissioner of Patents

